It is well recognized that the physiological repair of bone defects and fractures is mediated by factors which encourage the differentiation of cells and the formation of the mineral components of bone. Recently, attempts have been made to identify the factor or factors which are significant in these activities. U.S. Pat. Nos. 4,440,750 and 4,430,760 disclose the use of demineralized bone powder (DMB) to substitute for whatever naturally occurring factors are required in implants or by injection. U.S. Pat. Nos. 4,294,753 and 4,455,256 to Urist disclose a bone morphogenic protein (BMP) which is extracted from demineralized bone using urea or guanidine chloride, and then reprecipitated. Further purifications of this factor have been reported by Urist in Clin Orthop Rel Res (1982) 162: 219; Science (1983) 220: 680; and Proc Natl Acad Sci (USA) 81: 371. Osteogenic factor proteins which have characteristics different from those described by Urist for BMP were isolated from DMB and purified by Seyedin and Thomas (U.S. Pat. No. 4,434,094; U.S. Pat. No. 4,627,982).
Since the foregoing factors aid in the reformation of bone, it has been desirable to include them in compositions administered for bone repair. In U.S. Pat. No. 4,440,750 (supra) a reconstituted atelopepetide collagen preparation was used as a carrier for either DMB or a DMB extract. U.S. No. 4,394,370 to Jefferies discloses a nonatelopeptide collagen composition as a carrier for crude extract of DMB, which is referenced to the Urist publications.
Additional work has been done by Reddi, et al, Proc Natl Acad Sci (1983) 69: 1601 which describes the use of allogenic demineralized bone powder in rat-host animals; Sampath, T. K. et al (Proc Natl Acad Sci (USA)) (1983) 80: 6591 reported further purification of the osteogenic factors from a number of species.
U.S. Pat. No. 4,563,350 (of which this is a continuation-in-part) describes the use of a collagen bone repair composition which, however, requires the presence of nonfibrillar collagen to deliver the inductive activity effectively. The parent application to the herein specification, U.S. Ser. No. 816,268, filed 6 Jan. 1986, assigned to the same assignee and incorporated herein by reference, describes compositions containing, in addition to hypoimmunogenic nonfibrillar or fibrillar collagen, at least 75% wt/wt of mineral for hard tissue implants. The preparations described in that application are prepared by processes which do not require, and do not recognize the desirability of, adequate intimate mixing under conditions which prevent separation of the collagen and mineral components of the carrier. In suggested preparations described in that application, collagen in solution at approximately 3 mg/ml, which also contains the osteogenic factor is mixed with solid mineral powder and the resulting material is lyophilized. In the alternative, a paste is prepared using a lyophilized mixture of mineral with the osteogenic factor and this is added to a 65 mg/ml Zyderm.RTM. collagen implant fibrillar collagen suspension.
Collagen/mineral preparations for conductive repair of bone--i.e., matrices which permit the ingrowth of new cartilage and bone cells, but without the introduction of exogenous osteoinductive factors have also been described. U.S. Ser. No. 848,443, filed 4 Apr. 1986, which is a continuation-in-part of U.S. Ser. No. 717,072, now abandoned, assigned to the same assignee and incorporated herein by reference, describes the preparation of wet and dry mixtures of mineral and atelopeptide collagen which contain 60-98% by weight of mineral and 2-40% of collagen. The compositions are prepared by a mixing the collagen suspension at 65 mg/ml with the solid powdered mineral. The resulting mixtures are either used as a paste, or are allowed to dry at ambient temperature and pressure.
U.S. No. 4,485,097 to Bell describes a collagen lattice containing fibroblast cells and demineralized bone powder. However, this has no mineral content.
U.S. Pat. No. 4,097,935 describes a hydroxyapatite ceramic material which can be mixed with collagen to obtain a bone replacement mixture.
None of the foregoing compositions result in a homogeneous, rigid preparation which can be used directly for implantation in bone, and which is effective in the mediation of bone repair by effective delivery of the included osteogenic factors.